Medikine will use SBIR funding to develop a novel therapeutic approach for treating diabetic nephropathy (DN) - a major life-threatening complication of diabetes, and the leading cause of chronic kidney disease and kidney failure in the United States. In 2008 DN accounted for 44% of all new cases of kidney failure, and more than 200,000 of these patients were treated with chronic dialysis or kidney transplant. The cost of managing DN is enormous, estimated to be $16.8B in the U.S. in 2004. Treatment options are limited, and consist of a combination of increased adherence to glycemic control measures, and administration of anti-hypertensive agents. While these therapies slow the progression, the disease is often inexorable, leading to end stage renal disease. Therefore, there is a large and growing unmet medical need for more effective therapeutic options to address DN, and to avoid the profound and severely debilitating consequences of kidney failure. Medikine will address this need by developing novel peptide mimics of bone morphogenic protein 7 (BMP7) - a key cytokine in the TNFb superfamily that has the ability to halt, and even reverse, the progression of renal fibrosis, which is the primary cause of kidney failure in DN patients. Damage to renal tissue, such as occurs with diabetes patients, causes an increase in local production of TGFb1, and this in turn initiates and maintains kidney fibrosis. Remarkably, in a variety of animal models of kidney injury, BMP7 treatment was reported to reverse existing structural damage, and to restore renal function. However, the pro-fibrotic effector CTGF binds to BMP7, blocking anti-fibrotic activity, and complicating the development of BMP7 itself as an anti-fibrotic agent. Medikine proposes to overcome CTGF interference by creating small peptide mimics of BMP7 (10 to 20 residues) that are not bound or inhibited by CTGF, are unrelated to peptide sequences present in BMP7, and that will evade this regulatory process to provide a novel anti-fibrotic therapy for DN. In Phase I of this SBIR proposal, we will identify a set of peptide ligands, each of which is highly selective for one of the six receptor subunits that can bind BMP7. This will be done by screening the extracellular domains (ECDs) of these receptors against large, random peptide libraries. Information from the peptide binding SAR will be used to design and construct a set of secondary libraries, each enriched in peptides specific to one of the subunits; and a counter-selective screening technology will be employed to optimize peptide selectivity and affinity for each respective subunit. These subtype-selective ligands will then be chemically dimerized in a number of heteromeric configurations to identify agonists of BMP7 receptors. The Medikine Phase II project will focus on further optimization and characterization of the heterodimeric agonists, testing them in animal models of renal fibrosis, and selecting a candidate for clinical development. PUBLIC HEALTH RELEVANCE: Diabetic nephropathy (DN) is a major life-threatening complication of diabetes, is the leading cause of chronic kidney disease and kidney failure in the United States, and is the leading reason for treating patients with chronic dialysis or kidney transplant. A naturally occurring protein called bone morphogenic protein 7 that has the ability to halt, and even reverse, the kidney damaging effects of DN has recently been discovered, but its potential use as a drug is compromised by other naturally occurring proteins that block its beneficial effect. Medikine will develop a novel peptide mimetic of BMP7 that retains the therapeutic potential of the protein, but will not be blocked by other naturally occurring proteins and therefore will represent a novel therapeutic approach for treating DN.